Piperidine derivatives and preparation



2,798,073 Patented July 2, 19 7 IIPERIDINE DERIVATIVES AND PREPARATIONTHEREOF John Lee, Essex Fells, and Albert Ziering, Nutley, N. 3.,assignors to Hotfmann-La Roche Inc., Nutley, N. J., a corporation of NewJersey No Drawing. Application January 31, 1955,

Serial No. 485,308

15 Claims. (Cl. 260-2943) This invention relates to novel chemicalcompounds, and to novel processes and novel intermediates in thepreparation thereof.

An important aspect of the invention relates to bases of the class 1methyl 3 allyl 4 phenyl 4 alkanoyloXy-p iperidine wherein the alkanoylradical contains from 2 to 4 carbon atoms, and to acid addition saltsthereof. These bases and their acid addition salts are useful asmedicinals, more particularly as analgesic compounds; characterized bytheir excellent analgesic activity, quick onset of the analgesic action,relatively short duration of the analgesic action, and relative absenceof hypnotic action.

Another aspect of the invention relates to novel processes useful inmaking the above identified bases and acid addition salts.

Still a further aspect of the invention relates to novel intermediatesuseful in the preparation of the above identified bases and acidaddition salts.

A comprehensive embodiment of the invention can be visualized in termsof the following flow sheet, wherein- R represents a lower alkylradical,

R represents a lower alkyl radical,

M represents a monovalent radical selected from the class of Li andMg-halide radicals, and

R represents an alkyl radical having from 1 to 3 carbon atoms. 1

FLOW SHEET CHz=C-COO R1 m-on=cu,

Lower alkyl a-allylacrylate Lower alkyl a-a1lyl-Bmethyl-amino-propionatel CH2=CH-C o 0 R Lower alkyl acrylate LlNHg or aNH as condensing agent)2. hydrolyze and decarborylate I C Hz-C H=C Hz1methyl-3nllyl-4-piperldone 11. CaHa-M Organometallo-phenyl compound 2.hydrolyze GET-CH OKs-N cur-on C6Hl Hz-CH=CH11methyl-3-al1y1-4-phenylA-hydroxy-plperidine l (RC0)2O Acylating agent(VI) Agni-( 152 /0COR CHa-N1 clan-on can CHPCH=CH21-methyl-3-allyl-4phenyl-4-alkanoyloxy-piperidine In the embodimentgraphically represented by the above flow sheet, the invention providesa process for making 1 methyl 3 allyl 4 phenyl 4 alkanoyloxy piperidinewherein the alkanoyl radical contains from 2 to 4 carbon atoms, whichcomprises the steps of condensing lower alkyl u-allylacrylate (I) withmethylamine thereby producing lower alkyla-allyl-fi-methylaminopropionate (II), condensing the latter with loweralkyl acrylate thereby producing di(lower alkyl)a-allyl-fi,pmethylimino-dipropionate (III), subjecting the latter toring closure thereby producing 1-methyl-3-allyl-4-piperidone (IV),reacting the latter with an organometallophenyl compound CsH5M, as abovedefined, and hydrolyzing thereby producing l-methyl-3allyl-4-phenyl-4-hydroXy-piperidine (V), and reacting the latter with an acylating agentwherein the acylradical is an alkanoyl radical having from 2 to 4 carbonatoms thereby producing 1methyl-3-allyl-4-phenyl-4aalkanoyloxy-piperidine wherein the alkanoylradical has from 2 to 4 carbon atoms (VI).

A preferred form of the process described in the flow sheet comprisescondensing ethyl a-allyl-acrylate with methylamine thereby producingethyl oa-allyl-B-methylamino-propionate, condensing the latter withethyl acrylate thereby producing diethyl u-allyl-fi,fl'-methyliminodipropionate, subjecting the latter to ring closure by heating in thepresence of sodium thereby producingcarbethoxy-1-methyl-3allyl-4-piperidone, heating the latter in diluteaqueous acidic medium with a mineral acid (preferably dilute aqueoushydrochloric or hydrobromic acid) thereby producing an addition salt of1-methyl-3- allyl-4-piperidone with said mineral acid, neutralizing saidacid addition salt of 1methyl-3allyl-4-piperidone thereby releasing thefree base, condensing the resulting 1 methyl 3 allyl 4 piperidone withlithium phenyl, and hydrolyzing the resulting lithiumoxy condensationproduct thereby producing l-methyl-3allyl-4-phenyl-4-hydroxy-piperidine, and reacting the resulting l-methyl-3-allyl-4-phenyl-4hydroxy-piperidine with an acid anyhydride wherein the:acyl radical is an alkanoyl radical having from 2 to 4 carbon atoms. 1

1 methyl- 3allyl-4phenyl-4-alkanoyloXy-piperidine,

Formula VI above, is a base which readily forms acid addition salts withacids. Particularly preferred for use in me.- dicinal compositions arethe acid addition salts of said base of Formula VI with non-toxic acidsof the type conventionally employed in the preparation of medicinallyuseful salts of pharmacologically active bases; e. g. strong mineralacids, such as hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid and phosphoric acid, and organic acids such as aceticacid, palmitic acid, malic acid, tartaric acid, oxalic acid, citricacid, d-camphorsulfonic acid, ethanesulfonic acid, and the like.

The bases represented by Formulas ll, Ill, IV and V above likewiseformacid addition salts with acids. The acids ordinarily preferred toform addition salts when using these bases as intermediates, e. g. inprocedures for manufacturing or purifying said base intermediates, arethe strong mineral acids, such as hydrochloric, hydrobromic, nitric,sulfuric and phosphoric acids. When effecting resolution of opticalantipodes, it is of course desirable to use optically active organicacids, e. g. dor l-tartaric acid, d-camphorsulfonic acid, etc.

The base represented by Formula IV in the above flow sheet has a centerof asymmetry at carbon atom 3. The bases represented by Formulas V andVI in the above flow sheet have two centers of asymmetry at carbon atoms3 C./ 30 mm. Hg was 1-methyl-3-ally1-4-piperidone. Yield: 383 g. (34.5percent of theory).

Example 4 383 g. of 1-methyl-3-allyl-4-piperidone was added dropwise tothe whole of a solution of phenyl lithium, pre pared from 52.5 g. oflithium and 588 g. of bromobenzene, in 4 liters of dry diethyl ether atC. After the addition, 500 cc. of water was added; then the ether layerand 4. Accordingly, all of these bases, and the acid addition saltsderivedtherefrom, can exist in a number of stereoisomeric forms. Itshould be understood that the invention embraces generically all of thestereoisomeric forms of the novel compounds graphically represented inthe above flow sheet.

The invention is further disclosed in the following examples, which areillustrative but not limitative thereof:

Example 1 545 g. of the known compound ethyl a-allylacrylate wasdissolved in 500 cc. of absolute ethanol, and the solution was added toa solution of 121 g. of methylamine in 500 cc. of absolute ethanol. Thereaction mixture was heated in an autoclave for 5 hours at 100 C. in anitrogen atmosphere under a pressure of 600 p. s. i. gauge. At the endof this time the solvent was driven oil and the residue was fractionatedunder reduced pressure. The fraction distilling at 115-1 19 C./ 35 mm.Hg was ethyl a-allyl-B-methylamino-propionate. Yield: 507 g. (76 percentof theory).

Example 2 1385 g. of ethyl a-allyl-fi-methylamino-propionate was addedto 1100 g. of ethyl acrylate and the mixture was heated in an autoclaveat 100 C. for 6 hours in a nitrogen atmosphere under a pressure of 600p. s. i. gauge. The reaction mixture was then distilled under reducedpressure. The fraction distilling at 141-146 C./4 mm. Hg was diethyla-allyl-fi,/3'-methylimino-dipropionate. Yield: 1962 g. (90 percent oftheory).

Example 3 1962 g. of diethyl a-allyl-fi,,8'-methylimino-dipropionate wasadded in a slow stream to 167 g. of sodium shot in 4 liters of tolueneheated initially to 90 C. The diester was added at such a rate that thereaction mixture refiuxed gently. After the addition had been completed,the reaction mixture was cooled to 30 C. and the whole of a hydrochloricacid solution, formed by diluting 1770 cc. of concentrated (37 percentaqueous) hydrochloric acid to 4 liters, was added. The toluene layer wasseparated, and the aqueous acidic solution was refluxed until a drop ofthe solution, diluted with 1 cc. of Water, was not colored by theaddition of a drop of a 1 percent solution of ferric chloride. Thereaction mixture was then concentrated in vacuo to about 500 cc.,cooled, and 50 percent aqueous sodium hydroxide solution was addedthereto until the solution was strongly alkaline (pH 12). An oilseparated, which was extracted with ether. The ether extract was driedover anhydrous potassium carbonate, the solvent was removed, and theresidue was distilled in vacuo. The fraction distilling at 11 211'6 wasseparated and dried over anhydrous potassium carbonate. The ether wasdistilled off and the residue was crystallized from petroleum ether (B.P. -80 C.). Upon filtration,dl-u-1-methyl-3-allyl-4-phenyl-4-hydroxypiperidine remained upon thefilter. M. P. Ill-112 C. Yield: 300 g. (52 percent of theory). (The moredifficultly soluble stereoisomeric form, which crystallizes out first,is here arbitrarily designated the a-form; its diastereoisomer isdesignated the ,B-form.)

The filtrate, upon concentration, yielded a mixture of the dl-uanddl-B-isomers, M. P. 95 C. Yield: 100 g. By repeated crystallizations,dl-B-l-methyl 3 allyl-4- phenyl-4-hydroxy-piperidine was obtained inpure form, M. P. 86 C. (from petroleum ether, B. P. 30-60 C.).

Example 5 5 g. of dl-a-l-methyl-3-allyl-4-phenyl-4-hydroxy-piperidinewas added to 15 cc. of n-propionic anhydride and the solution was heatedon a steam bath for 5 hours. The excess propionic anhydride wasdistilled ofl? in vacuo and the residue was dissolved in diethyl ether.Dry hydrogen chloride gas was bubbled into the ether solution until nofurther precipitate was obtained. The precipitate of dl-u-1-methyl-3-allyl-4-phenyl-4-n-propionoxy piperidine hydrochloride wasrecrystallized from a mixture of acetone and methanol, M. P. 186l87 C.

dl-ot-l-methyl-3-allyl-4-phenyl-4-acetoxy-piperidine hydrochloride,similarly prepared by substituting for the propionic anhydride anequimolar proportion of acetic anhydride, melted at 210-211 C. afterrecrystallization from acetone.

dl-a-1-methyl-3-allyl-4-phenyl-4-n-butyroxy piperidine hydrochloride,similarly prepared by substituting for the propionic anhydride anequimolar proportion of n-butyric anhydride, melted at 151-153 C. afterrecrystallization from acetone.

By acylating dl-;9-1-methyl-3-allyl-4-phenyl-4-hydroxypiperidine withn-propionic anhydride and bubbling hydrogen chloride into the ethersolution of the base, using the same procedure as set forth in the firstparagraph of this example,dl-fi-1-rnethy1-3-allyl-4-phenyl-4-n-propionoxy-piperidine hydrochloridewas obtained, M. P. 206- 207 C. after recrystallization fromacetone-methanol.

1 g. of dl-a-l-methyl-3-allyl-4-phenyl-4-n-propionoxypiperidinedissolved in 1 cc. of ethyl acetate was mixed with 0.45 g. of dl-malicacid. The mixture was cooled and upon standingdl-a-1-methyl-3-allyl-4-phenyl-4-n-propionoxy-piperidine malatecrystallized out, M. P. 101- 1 g. ofdl-a-1-methyl-3-allyl-4-phenyl-4-n-propionoxypiperidine was mixed with0.31 g. of anhydrous oxalic acid in 5 cc. of diethyl ether. The reactionmixture was cooled and allowed to stand, whereupon dl-cz-1-methyl-3-allyl-4-phenyl-4-n-propionoxy-piperidine oxalate crystallized out, M. P.1-86187 C.

1 g. of dl-a-1-methyl-3-allyl-4-phenyl-4-n-propionoxypiperidine wasmixed with 0.23 cc. of concentrated aqueous (approximately 69 percent byweight) nitric acid in 5 cc. of diethyl ether. Upon cooling andstanding, dl-OC-1 methyl-3-allyl-4-phenyl-4-n-propionoxy-piperidinenitrate crystallized out, M. P. 194195 C.

We claim:

1. A process which comprises condensing lower alkyl a-allylacrylate withmethyla-mine thereby producing lower alkyla-allyl-p-methylamino-propionate, condensing the latter with lower alkylacrylate thereby producing di(lower alkyl)a-allyl-li,fi-methylimino-dipropionate, subjecting the later to ringclosure thereby producing 1-methyl-3- allyl-4-piperidone, reacting thelatter with an organometallo-phenyl compound and hydrolyzing therebyproducing 1-methyl-3-allyl-4-phenyl-4 hydroxy piperdine, and reactingthe latter with an acylating agent wherein the acyl radical is analkanoyl radical having from 2 to 4 carbon atoms thereby producing 1methyl 3 allyl 4 phenyl 4 alkanoyloxy piperidine wherein the alkanoylradical has from 2 to 4 carbon atoms.

2. A compound selected from the group consisting of lower alkylwallyl-fl-methylamino-propionate and acid addition salts thereof.

3. A process of making lower alkyl a-allyl-B-methylamino-propionatewhich comprises condensing lower alkyl ot-allylacrylate withmethylamine.

4. A compound selected from the group consisting of di(lower alkyl)a-allyl-flfl,'-methyliminodipropionate and acid addition salts thereof.

5. A process of making di(lower alkyl) methyl-18,5-methylimino-dipropionate which comprises condensing lower alkyla-allyl-[B-methylamino-propionate with lower alkyl acrylate.

6. A compound selected from the group consisting of1-methyl-3-allyl-4-piperidone and acid addition salts thereof.

7. A process of making 1-methy1-3-allyl-4-piperidone which comprisessubjecting di(lower alkyl) ut-a11yl-,8, 3- methylimino-dipropionate toring closure.

8. A compound selected from the group consisting ofl-methyl-3-allyl-4-phenyl-4-hydroxy-piperidine and acid addition saltsthereof.

9. A process of making 1-methyl-3-allyl-4-phenyl-4- hydroxy-piperidinewhich comprises reacting 1-methyl-3- allyl-4-piperidone with anorganometallophenyl compound and hydrolyzing.

10. A compound selected from the group consisting of1-methyl-3-allyl-4-phenyl-4 alkanoyloxy piperidine wherein the alkanoylradical contains from 2 to 4 carbon atoms and acid addition saltsthereof.

11. 1-methyl-3-allyl-4-phenyl-4-alkanoyloxy-piperidine wherein thealkanoyl radical has from 2 to 4 carbon atoms.

12. A process of making a compound according to claim 11 which comprisesreacting 1-rnethyl-3-allyl-4- phenyl-4-hydroxy-piperidine with anacylating agent wherein the acyl radical is an alkanoyl radical havingfrom 2 to 4 carbon atoms.

13. An acid addition salt of a compound according to claim 11.

14. l-methyl-3-allyl-4-phenyl-4-n propionoxy piperidine.

15. An acid addition salt of a compound according to claim 14.

Lee Feb. 21, 1950 Lee Feb. 21, 1950

1. A PROCESS WHICH COMPRISES LOWER ALKYL A-ALLYLACRYLATE WITHMETHYLAMINE THEREBY PRODUCING LOWER ALKYLA-ALLYL-B-METHYLAMINO-PROPIONATE, CONDENSING THE LATTER WITH LOWER ALKYLACRYLATE THEREBY PRODUCING DI(LOWER ALKYL)A-ALLYL-B,B''-METHYLIMINO-DIPROPIONATE, SUBJECTING THE LATTER TO RINGCLOSURE THEREBY PRODUCING 1-METHYL-3ALLYL-4-PIPERIDONE, REACTING THELATTER WITH AN ORGANOMETALLO-PHENYL COMPOUND AND HYDROLYZING THEREBYPRODUCING 1-METHYL-3-ALLYL-4- HYDROXY- PIPERDINE, AND REACTING THELATTER WITH AN ACYLATING AGENT WHEREIN THE ACYL RADICAL IS AN ALKANOYLRADICAL HAVING FROM 2 TO 4 CARBON ATOMS THEREBY PRODUCING 1- METHYL-3-ALLYL -4PHENYL- 4 - ALKANOYLOXY - PIPERIDINE WHEREIN THE ALKANOYLRADICAL HAS FROM 2 TO 4 CARBON ATOMS.